EP0047216B1 - Method of selectively increasing yield and purity of certain cryoprecipitate proteins - Google Patents
Method of selectively increasing yield and purity of certain cryoprecipitate proteins Download PDFInfo
- Publication number
- EP0047216B1 EP0047216B1 EP81401370A EP81401370A EP0047216B1 EP 0047216 B1 EP0047216 B1 EP 0047216B1 EP 81401370 A EP81401370 A EP 81401370A EP 81401370 A EP81401370 A EP 81401370A EP 0047216 B1 EP0047216 B1 EP 0047216B1
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- European Patent Office
- Prior art keywords
- plasma
- ahf
- cryoprecipitate
- clg
- peg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/16—Blood plasma; Blood serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/829—Blood
- Y10S530/83—Plasma; serum
Definitions
- This invention relates to a method for the production of antihemophilic factor (AHF or Factor VIII) and cold-insoluble globulin (Clg or fibronectin).
- AHF or Factor VIII antihemophilic factor
- Clg or fibronectin cold-insoluble globulin
- AHF can thus be prepared from single units if plasma in routine blood banking procedures such as in closed bag collection systems as illustrated, e.g., in U.S. Patent 3,986,506 and 4,025,618, or concentrates can be prepared commercially on a large scale as described by Brinkhous et al., J. Amer. Med. Assn. 205, 613-617 (1968) and in U.S. Patent 3,631,018.
- cryoprecipitation procedures have been combined with fractionation methods that employ various chemical agents such as, e.g., ammonium sulfate, glycine, alcohol, heparin and polycondensed polyglycols such as polyethylene glycol (PEG), polypropylene glycol (PPG) and mixed polyethylene-polypropylene glycols, the latter being block copolymers of ethylene oxide and polyoxypropylene which are available commercially under the trademark Pluronic@ from BASF Wyandotte Chemical Company.
- PEG polyethylene glycol
- PPG polypropylene glycol
- Pluronic@ from BASF Wyandotte Chemical Company
- Patent 3,631, 018 while similar disclosure of the Pluronic polymers and their use in the production of AHF from cryoprecipitate can be had by reference to U.S. Patent 4,073,886. Disclosures of the use of heparin in the production of AHF from cryoprecipitate can be had by reference to US. Patents 3,803,115, 4,203,891 and Re. 29,698.
- Clg or fibronectin Another blood protein which precipitates from plasma in the cold is known as cold-insoluble globulin (Clg or fibronectin). This is an opsonic plasma factor not identified as Q2-surface binding globulin. Collection of the starting plasma in the aforesaid polycondensed polyglycols and/or heparin prior to cryoprecipitation also results in precipitation of the Clg with the AHF. Recent comments and reports on the importance of Clg have been published by Rock and Palmer, Thrombosis Res. 18. 551-556 (1980) and Anon., Hospital Pract. 4(7), 35-36 (1980). See also U.S. Patent 4,210,580.
- EP-A-18561 which was published after the priority data claimed in the present specification, discloses a method for separating fibrinogen from AHF, where the suspended cryoprecipitate is subjected to a glycine type precipitation step with the presence of a mono- or aligo- saccharide or sugar alcohol before the heat treatment. This step eliminates an important part of the total fibrinogen but also results in a loss of AHF.
- the cryoprecipitate is reconstituted in aqueous solution and then subjected to a heat treatment step at a temperature of from 45°C to 56°C or even 60°C, and preferably at about 50°C, for a period of from one to sixty minutes, followed by removal of the resulting precipitate of contaminating proteins and recovery of the desired AHF- and Clg-containing supernatent.
- Aqueous solutions containing a combination of glycine, a or j3 alanine, hydroxyproline, proline, glutamine, a, p or y-aminobutyric acid and a mono- or oligosaccharide or sugar alcohol are excluded.
- the aqueous solution for reconstitution can be, e.g., pyrogen-free water, physiologically normal saline (0.9% NaCI), citrated saline solution (e.g., one part of 0.1 molar sodium citrate in four parts by weight normal saline), tris buffer at pH of about 7, or other physiologically acceptable aqueous solutions which are compatible with AHF and Clg.
- physiologically normal saline 0.9% NaCI
- citrated saline solution e.g., one part of 0.1 molar sodium citrate in four parts by weight normal saline
- tris buffer at pH of about 7, or other physiologically acceptable aqueous solutions which are compatible with AHF and Clg.
- the cryoprecipitate refers to the precipitate obtained from the freezing and cold thawing of human or animal blood plasma, and separated from the supernatant fraction of the plasma, as well as concentrates of the cryoprecipitate.
- the cryoprecipitate is preferably obtained by the rapid freezing of fresh plasma although stored plasma can also be used.
- the freezing is usually carried out at temperatures of from about -20°C to about -80°C, followed by slow thawing at about 4°C.
- the starting plasma preferably is collected and processed with a polycondensed polyglycol such as PEG and/or Pluronic polymer and/or heparin as described in U.S. Patents 4,086,218; 4,105,650; 4,137,223; and 4,189,425.
- a polycondensed polyglycol such as PEG and/or Pluronic polymer and/or heparin as described in U.S. Patents 4,086,218; 4,105,650; 4,137,223; and 4,189,425.
- PEG 4000 is a preferred polyol but PEG having molecular weights of from about 2000 to about 10,000 also can be used.
- Pluronic F68 polyol having a polyoxypropylene base molecular weight of about 1750, a polyoxyethylene content of about 80%, and a total molecular weight of about 8750 also is a preferred polyol, but similar such polyols having a polyoxyethylene content as low as about 10% can be used provided that in such case the polyoxypropylene molecular weight is not greater than about 1750.
- the polyoxyethylene content is about ' 20% or higher and the polyoxypropylene molecular weight is from about 900 to about 4000.
- the total molecular weight of these block copolymers preferably lies within the range of from about 2000 to about 10,000.
- one unit of heparin is defined to mean one U.S.P. (United States Pharmacopoeia) unit.
- the U.S.P. unit of heparin is the quantity that will prevent 1.0 ml of citrated sheep plasma from clotting for one hour after the addition of 0.2 ml of a 1:100 CaC1 2 solution.
- heparin also is meant to include the sodium salt of heparin, the latter substance being preferred due to its water solubility.
- the precipitate of contaminating proteins is removed, for example, by centrifugation, filtration and the like separation procedures, and the clarified supernatant is retained as a purified ANH- and Clg-containing concentrate.
- This concentrate can then be frozen and stored for later use, or further processed according to conventional procedures known in the art or used directly for administration to a patient.
- the AHF- and Clg-containing fraction can be heated to about 60°C for at least about five minutes to inactivate the AHF without substantial loss of the Clg.
- the starting material for recovery of a Clg concentrate can also be a cryoprecipitate concentrate from which a substantial portion of the fibrinogen has been precipitated in accordance with the method described in U.S. Patent 4,188,318.
- AHF is separated from fibrinogen and its denatured and degraded products by collecting the cryoprecipitate in low ionic strength solution. After removal of lipds and pro- thrombin complex by adsorption, fibrinogen and its denatured and degraded products are then selectively precipitated in the cold while AHF remains in solution. This precipitate also contains Clg.
- the method of the present invention can then be used on this AHF-poor cryoprecipitate concentrate to inactivate the fibrinogen and its denatured and degraded products without substantial destruction of the Clg.
- the presence of the polycondensed polyglycol and/or heparin enhances the heat denaturation of fibrinogen while preventing co-precipitation or destruction of AHF and Clg during the heating step.
- Fresh human blood is collected in a donor blood bag containing a small amount of anticoagulant solution (CPD preservative solution).
- CPD preservative solution a small amount of anticoagulant solution
- the cells are spun down by centrifugation and the plasma supernatant is expressed into a satellite blood bag.
- 200-250 ml of whole plasma thus collected is admixed with PEG 4000 to a concentration of about 2% by weight of the polyol (Carbowax 4000, Union Carbide).
- the treated plasma is subjected to a temperature between -20° and -50°C to effect rapid freezing. Once frozen, the plasma is subjected to a temperature between +2° and +4°C for cold thawing to produce a cryoprecipitate.
- the supernatant plasma is then removed from the cryoprecipitate by decantation.
- the retained cryoprecipitate can be frozen and stored for later reconstitution and heat treatment or it can be reconstituted and heat treated immediately as follows:
- the cryoprecipitate is first reconstituted with about one to three volumes of pyrogen-free water (or other physiologically acceptable aqueous solution) per gram of cryoprecipitate. Although dissolution can be had at ambient temperature, warming to about 37°C is used to accelerate dissolution.
- the reconstituted cryoprecipitate is then subjected to the heat treatment step by heating in a water bath, although other apparatus such as incubating ovens, steam jacketed vessels and the like equipment can be used for larger scale amount of cryoprecipitate.
- the temperature during this heat treatment step is maintained from 45° to 56°C, and preferably at 50°C for one to sixty minutes.
- the one to sixty minute period of heat treatment can be calculated from the time that opalescence or precipitation is first observed, thus signifying the beginning of fibrinogen denaturation.
- the preparation can be centrifuged for clarification, or the supernatant can be directly aspirated into a syringe (which can contain a filter).
- the final preparation can be administered to the patient directly or refrozen for later use.
- the method of the invention is able to achieve a desirable selective separation of cryoprecipitate proteins.
- Example 1 The procedure of Example 1 is repeated except that an equal amount of Pluronic F-68 is substituted for the PEG 4000 in the starting plasma to produce substantially similar results.
- Example 1 The procedure of Example 1 is repeated except that 125 to 250 units of heparin are added to the 200 to 250 ml of starting plasma with substantially similar results.
- Example 2 The procedure of Example 2 is repeated except that 125 to 250 units of heparin are added to the 200 to 250 ml of starting plasma with substantially similar results.
- Example 1 The procedure of Example 1 is repeated except that 125 to 250 units of heparin are added to the 200 to 250 ml of starting plasma without any PEG 4000 or other polycondensed polyglycol added to the plasma with substantially similar results.
Abstract
Description
- This invention relates to a method for the production of antihemophilic factor (AHF or Factor VIII) and cold-insoluble globulin (Clg or fibronectin).
- For a number of years, cryoprecipitation as described by Pool et al. has been a principal method for the isolation and partial purification of AHF. Nature, London 203,312 (1964); New Eng. J. Med. 273, 1443-7 (1965). AHF can thus be prepared from single units if plasma in routine blood banking procedures such as in closed bag collection systems as illustrated, e.g., in U.S. Patent 3,986,506 and 4,025,618, or concentrates can be prepared commercially on a large scale as described by Brinkhous et al., J. Amer. Med. Assn. 205, 613-617 (1968) and in U.S. Patent 3,631,018.
- In order to obtain more highly purified concentrates of AHF, the cryoprecipitation procedures have been combined with fractionation methods that employ various chemical agents such as, e.g., ammonium sulfate, glycine, alcohol, heparin and polycondensed polyglycols such as polyethylene glycol (PEG), polypropylene glycol (PPG) and mixed polyethylene-polypropylene glycols, the latter being block copolymers of ethylene oxide and polyoxypropylene which are available commercially under the trademark Pluronic@ from BASF Wyandotte Chemical Company. Further description of PEG and its use in the production of AHF from cryoprecipitate can be had by reference to U.S. Patent 3,631, 018, while similar disclosure of the Pluronic polymers and their use in the production of AHF from cryoprecipitate can be had by reference to U.S. Patent 4,073,886. Disclosures of the use of heparin in the production of AHF from cryoprecipitate can be had by reference to US. Patents 3,803,115, 4,203,891 and Re. 29,698.
- It is known that during the production of AHF from cryoprecipitate there is an inevitable loss of AHF related to the further purification steps. Although these purification procedures may appear to be simple, they require great care to harvest an optimal amount of AHF. As noted recently by Johnson et al., of the New York University Medical Center, isolation of AHF by large scale techniques results in a maximum yield of about 30% and most large scale producers have obtained a yield of only 20% to 25%. Vox Sang. 36, 72-76 (1979). Thus it is desirable to develop some process which would allow removal of unwanted or unnecessary proteins (such as fibrinogen and its denatured and degraded products) from an AHF concentrate without undue loss of the valuable AHF itself. One approach to this goal is to produce a cryoprecipitate which contains increased amounts of AHF as described in recent U.S. Patents 4,086,218; 4,105,650; 4,137,223; 4,189,425; and by Johnson et al., Vox Sang 36, 72-76 (1979). As disclosed in these patents and publication, small amounts of PEG and/or Pluronic polymers with or without added heparin are employed in the plasma prior to carrying out the freezing process to produce the cryoprecipitate. These procedures thereby result in a higher yield of cryoprecipitate and an associated greater amount of AHF. However, other proteins (e.g., fibrinogen and its derivatives) normally found in the cryoprecipitate are also proportionally increased. Methods normally used to remove the unwanted proteins (such as the precipitation with glycine, PEG and alcohol) unfortunately also remove a proportional amount of AHF by co-precipitation with no real net gain in the final yield of AHF.
- Another blood protein which precipitates from plasma in the cold is known as cold-insoluble globulin (Clg or fibronectin). This is an opsonic plasma factor not identified as Q2-surface binding globulin. Collection of the starting plasma in the aforesaid polycondensed polyglycols and/or heparin prior to cryoprecipitation also results in precipitation of the Clg with the AHF. Recent comments and reports on the importance of Clg have been published by Rock and Palmer, Thrombosis Res. 18. 551-556 (1980) and Anon., Hospital Pract. 4(7), 35-36 (1980). See also U.S. Patent 4,210,580. EP-A-18561, which was published after the priority data claimed in the present specification, discloses a method for separating fibrinogen from AHF, where the suspended cryoprecipitate is subjected to a glycine type precipitation step with the presence of a mono- or aligo- saccharide or sugar alcohol before the heat treatment. This step eliminates an important part of the total fibrinogen but also results in a loss of AHF.
- In accordance with the present invention it has been unexpectedly found that fibrinogen and its denatured and degraded products, which are the primary contaminating proteins of cryoprecipitation, are also uniquely thermoreactive whereby they can be selectively thermally removed from the cryoprecipitate without substantial loss of AHF or Clg activities. According to the method of the invention, the cryoprecipitate is reconstituted in aqueous solution and then subjected to a heat treatment step at a temperature of from 45°C to 56°C or even 60°C, and preferably at about 50°C, for a period of from one to sixty minutes, followed by removal of the resulting precipitate of contaminating proteins and recovery of the desired AHF- and Clg-containing supernatent. Aqueous solutions containing a combination of glycine, a or j3 alanine, hydroxyproline, proline, glutamine, a, p or y-aminobutyric acid and a mono- or oligosaccharide or sugar alcohol are excluded.
- The aqueous solution for reconstitution can be, e.g., pyrogen-free water, physiologically normal saline (0.9% NaCI), citrated saline solution (e.g., one part of 0.1 molar sodium citrate in four parts by weight normal saline), tris buffer at pH of about 7, or other physiologically acceptable aqueous solutions which are compatible with AHF and Clg.
- As used herein, the cryoprecipitate refers to the precipitate obtained from the freezing and cold thawing of human or animal blood plasma, and separated from the supernatant fraction of the plasma, as well as concentrates of the cryoprecipitate. The cryoprecipitate is preferably obtained by the rapid freezing of fresh plasma although stored plasma can also be used. The freezing is usually carried out at temperatures of from about -20°C to about -80°C, followed by slow thawing at about 4°C.
- During the freezing and cold thawing of plasma to form the cryoprecipitate, the starting plasma preferably is collected and processed with a polycondensed polyglycol such as PEG and/or Pluronic polymer and/or heparin as described in U.S. Patents 4,086,218; 4,105,650; 4,137,223; and 4,189,425. In these procedures, preferably from about 0.1 to about 25 grams of said polyol and/or from about 10 to about 2000 units of heparin are used per liter of plasma. PEG 4000 is a preferred polyol but PEG having molecular weights of from about 2000 to about 10,000 also can be used. Pluronic F68 polyol having a polyoxypropylene base molecular weight of about 1750, a polyoxyethylene content of about 80%, and a total molecular weight of about 8750 also is a preferred polyol, but similar such polyols having a polyoxyethylene content as low as about 10% can be used provided that in such case the polyoxypropylene molecular weight is not greater than about 1750. Preferably, the polyoxyethylene content is about '20% or higher and the polyoxypropylene molecular weight is from about 900 to about 4000. The total molecular weight of these block copolymers preferably lies within the range of from about 2000 to about 10,000.
- As used herein, one unit of heparin is defined to mean one U.S.P. (United States Pharmacopoeia) unit. The U.S.P. unit of heparin is the quantity that will prevent 1.0 ml of citrated sheep plasma from clotting for one hour after the addition of 0.2 ml of a 1:100 CaC12 solution. As used herein, the term "heparin" also is meant to include the sodium salt of heparin, the latter substance being preferred due to its water solubility.
- Following the heat treatment, the precipitate of contaminating proteins is removed, for example, by centrifugation, filtration and the like separation procedures, and the clarified supernatant is retained as a purified ANH- and Clg-containing concentrate. This concentrate can then be frozen and stored for later use, or further processed according to conventional procedures known in the art or used directly for administration to a patient.
- In those instances where a Clg fraction is desired without AHF, the AHF- and Clg-containing fraction can be heated to about 60°C for at least about five minutes to inactivate the AHF without substantial loss of the Clg.
- The starting material for recovery of a Clg concentrate can also be a cryoprecipitate concentrate from which a substantial portion of the fibrinogen has been precipitated in accordance with the method described in U.S. Patent 4,188,318. According to said method, AHF is separated from fibrinogen and its denatured and degraded products by collecting the cryoprecipitate in low ionic strength solution. After removal of lipds and pro- thrombin complex by adsorption, fibrinogen and its denatured and degraded products are then selectively precipitated in the cold while AHF remains in solution. This precipitate also contains Clg. The method of the present invention can then be used on this AHF-poor cryoprecipitate concentrate to inactivate the fibrinogen and its denatured and degraded products without substantial destruction of the Clg.
- Although it is not intended to be bound by theory, it is believed that the presence of the polycondensed polyglycol and/or heparin enhances the heat denaturation of fibrinogen while preventing co-precipitation or destruction of AHF and Clg during the heating step.
- The following examples will further illustrate the invention although it should be understood that the invention is not limited to these specific examples.
- Fresh human blood is collected in a donor blood bag containing a small amount of anticoagulant solution (CPD preservative solution). The cells are spun down by centrifugation and the plasma supernatant is expressed into a satellite blood bag. Then 200-250 ml of whole plasma thus collected is admixed with PEG 4000 to a concentration of about 2% by weight of the polyol (Carbowax 4000, Union Carbide). After gentle agitation to ensure complete mixing, the treated plasma is subjected to a temperature between -20° and -50°C to effect rapid freezing. Once frozen, the plasma is subjected to a temperature between +2° and +4°C for cold thawing to produce a cryoprecipitate. The supernatant plasma is then removed from the cryoprecipitate by decantation. The retained cryoprecipitate can be frozen and stored for later reconstitution and heat treatment or it can be reconstituted and heat treated immediately as follows:
- The cryoprecipitate is first reconstituted with about one to three volumes of pyrogen-free water (or other physiologically acceptable aqueous solution) per gram of cryoprecipitate. Although dissolution can be had at ambient temperature, warming to about 37°C is used to accelerate dissolution. The reconstituted cryoprecipitate is then subjected to the heat treatment step by heating in a water bath, although other apparatus such as incubating ovens, steam jacketed vessels and the like equipment can be used for larger scale amount of cryoprecipitate. The temperature during this heat treatment step is maintained from 45° to 56°C, and preferably at 50°C for one to sixty minutes. In order to facilitate uniform and optimum heat transfer or distribution, constant mixing of the solution is maintained during the heat treatment step by stirring or other such agitation. The one to sixty minute period of heat treatment can be calculated from the time that opalescence or precipitation is first observed, thus signifying the beginning of fibrinogen denaturation.
- Following the aforesaid heat treatment step, the preparation can be centrifuged for clarification, or the supernatant can be directly aspirated into a syringe (which can contain a filter). The final preparation can be administered to the patient directly or refrozen for later use.
- When heated as above at about 50°C for about thirty minutes, about 90% of the fibrinogen is denatured and only about 25% of the AHF activity is lost. When similarly heated for about forty minutes, 100% of the fibrinogen is denatured but still only about 25% of the AHF activity is lost. Thus the method of the invention is able to achieve a desirable selective separation of cryoprecipitate proteins.
- The procedure of Example 1 is repeated except that an equal amount of Pluronic F-68 is substituted for the PEG 4000 in the starting plasma to produce substantially similar results.
- The procedure of Example 1 is repeated except that 125 to 250 units of heparin are added to the 200 to 250 ml of starting plasma with substantially similar results.
- The procedure of Example 2 is repeated except that 125 to 250 units of heparin are added to the 200 to 250 ml of starting plasma with substantially similar results.
- The procedure of Example 1 is repeated except that 125 to 250 units of heparin are added to the 200 to 250 ml of starting plasma without any PEG 4000 or other polycondensed polyglycol added to the plasma with substantially similar results.
Claims (10)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT81401370T ATE12504T1 (en) | 1980-09-02 | 1981-09-01 | METHOD FOR SELECTIVE GROWING IN YIELD AND PURITY OF CERTAIN FREEZE-PRECIPITED PROTEINS. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/183,364 US4305871A (en) | 1980-09-02 | 1980-09-02 | Method of selectively increasing yield and purity of certain cryoprecipitate proteins by heating |
US183364 | 2002-06-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0047216A1 EP0047216A1 (en) | 1982-03-10 |
EP0047216B1 true EP0047216B1 (en) | 1985-04-03 |
Family
ID=22672507
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP81401370A Expired EP0047216B1 (en) | 1980-09-02 | 1981-09-01 | Method of selectively increasing yield and purity of certain cryoprecipitate proteins |
Country Status (6)
Country | Link |
---|---|
US (1) | US4305871A (en) |
EP (1) | EP0047216B1 (en) |
JP (1) | JPS57118520A (en) |
AT (1) | ATE12504T1 (en) |
CA (1) | CA1158977A (en) |
DE (1) | DE3169689D1 (en) |
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JPS57140724A (en) * | 1981-02-25 | 1982-08-31 | Green Cross Corp:The | Heat-treatment of aqueous solution containing cold insoluble globulin |
CA1178887A (en) * | 1981-10-01 | 1984-12-04 | Gail A. Rock | Factor viii concentrates prepared from heparinized plasma by the application of a cold precipitation technique |
US4481189A (en) * | 1982-04-14 | 1984-11-06 | New York Blood Center Inc. | Process for preparing sterilized plasma and plasma derivatives |
JPS5967228A (en) * | 1982-10-07 | 1984-04-16 | Green Cross Corp:The | Method for freeze-drying cold-insoluble globulin |
DE3467706D1 (en) * | 1983-04-28 | 1988-01-07 | Armour Pharma | Pharmaceutical preparation containing purified fibronectin |
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US4486410A (en) * | 1984-02-09 | 1984-12-04 | Armour Pharmaceutical Company | Heat defibrinogenation of AHF preparation |
US5149787A (en) * | 1984-05-22 | 1992-09-22 | The Blood Center Research Foundation | Method for maintaining intact, non-degraded factor VIII/von-Willebrand factor during blood processing |
US4710381A (en) * | 1984-05-22 | 1987-12-01 | The Blood Center Of Southeastern Wisconsin | Method for maintaining intact, non-degraded factor VIII/von-Willebrand factor during blood processing |
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US4749783A (en) * | 1986-07-11 | 1988-06-07 | Miles Laboratories, Inc. | Viral inactivation and purification of active proteins |
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US5151358A (en) * | 1989-06-13 | 1992-09-29 | Genencor International, Inc. | Processes for the recovery of naturally produced chymosin |
US5139943A (en) * | 1989-06-13 | 1992-08-18 | Genencor International, Inc. | Processes for the recovery of microbially produced chymosin |
US5770705A (en) * | 1996-11-01 | 1998-06-23 | Shanbrom Technologies Llc | Method for recovering proteins from plasma using insoluble, water-absorbing material |
US7297716B2 (en) * | 2000-10-23 | 2007-11-20 | Shanbrom Technologies, Llc | Enhanced production of blood components, blood cells and plasma without freezing |
US7411006B2 (en) * | 2000-10-23 | 2008-08-12 | Shanbrom Technologies, Llc | Enhanced production of blood clotting factors and fibrin fabric |
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US8389687B2 (en) * | 2000-10-23 | 2013-03-05 | Shanbrom Technologies, Llc | Polyvinylpyrrolidone cryoprecipitate extraction of clotting factors |
MXPA03007069A (en) * | 2001-02-07 | 2004-10-15 | Shanbrom Tech Llc | Carboxylic acid such as citric acid for desinfecting or enhacing the production of blood products such as plasma, cryoprecipitate or/and platelet. |
US6881573B2 (en) * | 2003-09-12 | 2005-04-19 | Allan L. Louderback | Augmented solvent/detergent method for inactivating enveloped and non-enveloped viruses |
EP1950225A1 (en) * | 2007-01-25 | 2008-07-30 | Octapharma AG | Method for increasing protein yield |
US20080306610A1 (en) * | 2007-06-07 | 2008-12-11 | Zimmer Orthobiologics, Inc. | Tissue processing for nonimmunogenic implants |
US8435305B2 (en) | 2010-08-31 | 2013-05-07 | Zimmer, Inc. | Osteochondral graft delivery device and uses thereof |
CN114746108A (en) * | 2019-09-20 | 2022-07-12 | 等离子体技术有限责任公司 | Therapeutic protein compositions and methods |
Citations (1)
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EP0018561A2 (en) * | 1979-04-25 | 1980-11-12 | BEHRINGWERKE Aktiengesellschaft | Process for the stabilization of blood clotting factors |
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US3631018A (en) * | 1970-05-01 | 1971-12-28 | Baxter Laboratories Inc | Production of stable high-potency human ahf using polyethylene glycol and glycine to fractionate a cryoprecipitate of ahf concentrate |
US3803115A (en) * | 1972-05-17 | 1974-04-09 | Baxter Laboratories Inc | Stabilization of ahf using heparin |
US4073886A (en) * | 1973-01-30 | 1978-02-14 | Baxter Travenol Laboratories, Inc. | Blood fractionation process using block copolymers of ethylene oxide and polyoxypropylene |
US4022758A (en) * | 1973-06-19 | 1977-05-10 | Ab Kabi | Isolation of coagulation factors I and VIII from biological material |
CA1007568A (en) * | 1973-12-13 | 1977-03-29 | Michael C. Attwell | Bovine immunoglobulin isolation process |
FR2279419A1 (en) * | 1974-07-25 | 1976-02-20 | Merieux Inst | Aggregate-free immunoglobulin prepns. - obtained by treatment with complement Clq factor or rheumatic factor |
US3986506A (en) * | 1974-09-03 | 1976-10-19 | Baxter Travenol Laboratories, Inc. | Apparatus for separation of cryoprecipitate from blood plasma and method |
US4025618A (en) * | 1974-09-03 | 1977-05-24 | Baxter Travenol Laboratories, Inc. | Method for separation of cryoprecipitate from blook plasma |
US4105650A (en) * | 1975-04-11 | 1978-08-08 | Edward Shanbrom, Inc. | Method of preserving blood plasma i |
US4189425A (en) * | 1975-04-11 | 1980-02-19 | Edward Shanbrom, Inc. | Method of preserving blood plasma I |
DE2527064C3 (en) * | 1975-06-18 | 1979-11-15 | Biotest-Serum-Institut Gmbh, 6000 Frankfurt | Process for the production of an intravenous native human immunoglobulin preparation with a natural half-life and unchanged antibody activity compared to the starting material |
NL7708005A (en) * | 1976-07-22 | 1978-01-24 | Monsanto Co | PROCESS FOR THE PREPARATION OF SERUM ALBUMIN. |
DK25877A (en) * | 1977-01-21 | 1978-08-15 | Nordisk Insulinlab | PROCEDURE FOR EXTRACTING PURE ALBUMIN FROM BLOOD PLASMA |
US4104266A (en) * | 1977-04-14 | 1978-08-01 | American National Red Cross | Method for preparation of antihemophilic factor |
US4137223A (en) * | 1977-05-16 | 1979-01-30 | Edward Shanbrom, Inc. | Method of preserving blood plasma II |
DE2857166T1 (en) * | 1977-11-17 | 1980-12-04 | Atomic Energy Authority Uk | PURIFICATION OF FACTOR VIII |
CA1074698A (en) * | 1977-12-19 | 1980-04-01 | Gail A. Rock | Method of collecting anti-hemophilic factor viii from blood and blood plasma |
-
1980
- 1980-09-02 US US06/183,364 patent/US4305871A/en not_active Expired - Lifetime
-
1981
- 1981-08-24 CA CA000384471A patent/CA1158977A/en not_active Expired
- 1981-09-01 DE DE8181401370T patent/DE3169689D1/en not_active Expired
- 1981-09-01 AT AT81401370T patent/ATE12504T1/en not_active IP Right Cessation
- 1981-09-01 EP EP81401370A patent/EP0047216B1/en not_active Expired
- 1981-09-02 JP JP56139207A patent/JPS57118520A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0018561A2 (en) * | 1979-04-25 | 1980-11-12 | BEHRINGWERKE Aktiengesellschaft | Process for the stabilization of blood clotting factors |
Also Published As
Publication number | Publication date |
---|---|
CA1158977A (en) | 1983-12-20 |
EP0047216A1 (en) | 1982-03-10 |
JPS57118520A (en) | 1982-07-23 |
DE3169689D1 (en) | 1985-05-09 |
ATE12504T1 (en) | 1985-04-15 |
US4305871A (en) | 1981-12-15 |
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